Injectable contraceptives are extensively used in Sub-Saharan Africa, where the incidence and prevalence of AIDS is high. There are many different forms of contraception, which vary in the method of delivery and type of synthetic compound (progestin). Progestins are designed to mimic the actions of progesterone, the active contraceptive ingredient. Clinical studies suggest that some, in particular the injectable contraceptive Depo Provera, but not other progestins, increase the risk of HIV-1 infection and transmission, particularly in young women. Young women are most at risk and also have the greatest need for effective contraception. Access to affordable and safe contraception is an enormous public health issue, affecting millions of women worldwide and particularly in the developing world. Since the current data from observational clinical studies do not provide sufficient information regarding the safety of hormonal contraceptives, particularly injectable medroxyprogesterone acetate (MPA) or Depo Provera, more research is urgently required to shed light on this important issue. Ex vivo studies on human female reproductive tract tissue likely represent the best method to obtain answers about the differential and direct effects and mechanisms of progestins on gene expression and cell functions relevant to HIV-1 acquisition. Steroid receptors, which control responses to progestins, play a key role in choice of progestin. Although different progestins exhibit similar mechanisms of action via the progesterone receptor, they have very different off-target effects on expression of genes that regulate immune function and many cellular processes, via binding to other steroid receptors, such as those for cortisol and androgens. This study will focus on the effects and mechanisms of action of four different progestins, at physiologically relevant concentrations, on expression of select genes previously identified as being important in HIV-1 transmission and pathogenesis in the female genital tract. Effects will be investigated in vitro, in several HIV-1 target cell and tissue model, including cervical tissue explants, primary genital epithelial cells, peripheral blood mononuclear cells and isolated T-cells and dendritic cells. Vaginal delivery of anti-retroviral (ARV) drugs as microbicides has emerged as a potentially effective prophylactic strategy. Vaginal delivery of a combined ARV with a progestin contraceptive offers an attractive strategy for both prevention of HIV-1 acquisition and prevention of pregnancy. However, limited information is available regarding the best choice of progestin contraceptive to combine with an ARV. Detailed ex vivo model studies are needed to define the optimal and safe combination of progestin and antiretroviral. Mechanistic studies addressing the effects on inflammation, integrity of the genita tract barrier, secretion of key defense molecules, and studies addressing how steroid receptor levels affect these processes will be performed. The results should provide key insights into choice of progestin alone and in combination with ARV for maximal protection of young women from HIV-1 infection.